Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease
Abstract Objective Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in...
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BMC
2025-05-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01222-5 |
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| author | Haifeng Lan Xiao-Jun Yu Guangsheng Ling Yuwei Zeng Yixi Yang Meiyang He Yixiao Yu Ming Shao |
| author_facet | Haifeng Lan Xiao-Jun Yu Guangsheng Ling Yuwei Zeng Yixi Yang Meiyang He Yixiao Yu Ming Shao |
| author_sort | Haifeng Lan |
| collection | DOAJ |
| description | Abstract Objective Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in modulating Runt-related Transcription Factor 2 (RUNX2)-driven osteogenesis in a CKD-MBD mouse model. Methods A CKD-MBD mouse model was established using 5/6 nephrectomy. Bioinformatic analysis of CKD-related datasets identified RUNX2 and USP7 as key genes implicated in bone metabolism. In vivo and in vitro experiments were conducted to assess the effects of CK2-mediated phosphorylation and USP7-induced deubiquitination on RUNX2 stability and function. Histomorphometry, Enzyme-Linked Immunosorbent Assay (ELISA), and micro-CT analyses were performed to evaluate bone density, strength, and metabolic markers. Results RUNX2 and USP7 were significantly downregulated in CKD-MBD mice. Silencing RUNX2 impaired osteoblast differentiation, reduced bone density, and increased bone turnover, while CK2 overexpression restored RUNX2 activity by phosphorylation, recruiting USP7 to stabilize RUNX2. Enhanced osteoblast differentiation and improved bone metabolism were observed in CKD-MBD mice upon CK2 activation. Conclusion CK2 activation promotes RUNX2 phosphorylation and stabilization by USP7, leading to improved osteogenesis and bone metabolism in CKD-MBD. Targeting the CK2/USP7/RUNX2 axis presents a potential therapeutic strategy for managing CKD-related bone disorders. |
| format | Article |
| id | doaj-art-8580be1d82d6425ea3df7e982a254e48 |
| institution | DOAJ |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj-art-8580be1d82d6425ea3df7e982a254e482025-08-20T03:22:03ZengBMCMolecular Medicine1528-36582025-05-0131111810.1186/s10020-025-01222-5Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney diseaseHaifeng Lan0Xiao-Jun Yu1Guangsheng Ling2Yuwei Zeng3Yixi Yang4Meiyang He5Yixiao Yu6Ming Shao7Department of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Spine Surgery, Honghui Hospital, Xi’an Jiaotong UniversityDepartment of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical UniversityDepartment of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical UniversityThe Third School of Clinical Medicine, Guangzhou Medical UniversityThe Third School of Clinical Medicine, Guangzhou Medical UniversityDepartment of Orthopedics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; The Third Affiliated Hospital, Guangzhou Medical UniversityAbstract Objective Chronic Kidney Disease (CKD) frequently leads to Mineral Bone Disorder (MBD), which significantly affects patient quality of life due to bone fragility and metabolic disturbances. This study investigates the role of Casein Kinase 2 (CK2) and Ubiquitin-Specific Protease 7 (USP7) in modulating Runt-related Transcription Factor 2 (RUNX2)-driven osteogenesis in a CKD-MBD mouse model. Methods A CKD-MBD mouse model was established using 5/6 nephrectomy. Bioinformatic analysis of CKD-related datasets identified RUNX2 and USP7 as key genes implicated in bone metabolism. In vivo and in vitro experiments were conducted to assess the effects of CK2-mediated phosphorylation and USP7-induced deubiquitination on RUNX2 stability and function. Histomorphometry, Enzyme-Linked Immunosorbent Assay (ELISA), and micro-CT analyses were performed to evaluate bone density, strength, and metabolic markers. Results RUNX2 and USP7 were significantly downregulated in CKD-MBD mice. Silencing RUNX2 impaired osteoblast differentiation, reduced bone density, and increased bone turnover, while CK2 overexpression restored RUNX2 activity by phosphorylation, recruiting USP7 to stabilize RUNX2. Enhanced osteoblast differentiation and improved bone metabolism were observed in CKD-MBD mice upon CK2 activation. Conclusion CK2 activation promotes RUNX2 phosphorylation and stabilization by USP7, leading to improved osteogenesis and bone metabolism in CKD-MBD. Targeting the CK2/USP7/RUNX2 axis presents a potential therapeutic strategy for managing CKD-related bone disorders.https://doi.org/10.1186/s10020-025-01222-5Chronic kidney diseaseMineral bone metabolism disorderCasein kinase 2Runt-related transcription factor 2Ubiquitin-specific protease 7 |
| spellingShingle | Haifeng Lan Xiao-Jun Yu Guangsheng Ling Yuwei Zeng Yixi Yang Meiyang He Yixiao Yu Ming Shao Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease Molecular Medicine Chronic kidney disease Mineral bone metabolism disorder Casein kinase 2 Runt-related transcription factor 2 Ubiquitin-specific protease 7 |
| title | Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease |
| title_full | Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease |
| title_fullStr | Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease |
| title_full_unstemmed | Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease |
| title_short | Targeting casein kinase 2 and ubiquitin-specific protease 7 to modulate RUNX2-mediated osteogenesis in chronic kidney disease |
| title_sort | targeting casein kinase 2 and ubiquitin specific protease 7 to modulate runx2 mediated osteogenesis in chronic kidney disease |
| topic | Chronic kidney disease Mineral bone metabolism disorder Casein kinase 2 Runt-related transcription factor 2 Ubiquitin-specific protease 7 |
| url | https://doi.org/10.1186/s10020-025-01222-5 |
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